Radical prostatectomy (RP) is a commonly used treatment option for localized prostate cancer. Unfortunately, the procedure carries a risk of post-surgical complications including a high risk of erectile dysfunction (ED). The main pathophysiological mechanism behind this is neuropraxia in which surgery either directly damages the cavernous nerves (CN) or does so indirectly through activation of an inflammatory response. Given that phosphodiesterase inhibitors (PDE5i), the mechanism of FDA-approved oral treatments for ED, are dependent on the production of nitric oxide (NO) from CN endings, the majority of patients undergoing RP where CN function is perturbed or lost are refractory to this treatment. In prior publications from our group we have demonstrated that topically applied particles delivering NO or a PDE5i can generate an erectile response in animal models of aging or RP. However, there is a strong rationale for combining both NO and PDE5i to treat ED in patients with neuropraxia: NO will initiate an erection and the PDE5i will maintain cyclic guanosine monophosphate (cGMP) levels, which activates biochemical pathways resulting in a sustained erection. The goal of the present proposal is to develop a novel therapeutic for treating ED: a topically applied microparticle (MP) delivery system delivering NO (NO-MP) with the potential to act cooperatively with PDE5i to treat ED in men that are refractory to current FDA-approved therapies. The goal of this proposal will be achieved through two specific aims. In Specific Aim 1, NO-MP will be formulated and optimized for clinical translation. NO-MP will be generated and loaded with four different concentrations of NO and tested in an animal model of RP (bilateral CN transected) to assess the ability to elicit erections. In addition, these animals will be used to perform preliminary pathology studies to provide initial evidence of safety of the NO-MP. In Specific Aim 2 it will be determined if a greater response can be obtained with a combination of NO-MP and a PDE5i (sildenafil) in promoting erectile function. At the conclusion of this phase I study, a lead NO concentration will be determined to develop a novel, topical therapeutic for neurogenic ED.